Recent studies have strengthened links between the pathogenesis of Alzheimer's disease (AD) and processing of beta-amyloid precursor protein (APP) leading to formation of amyloid beta-peptide (Abeta), especially increased levels of Abeta(1-42). A key element missing in this "amyloid hypothesis" of neuronal degeneration is the means by which low levels of Abeta perturb cellular functions; we hypothesize that Abeta interaction with cellular cofactors mediates these early events. The receptor RAGE is a multi-ligand member of the immunoglobin superfamily of cell surface molecules, and binds Abeta, showing highest affinity for beta-sheet fibrils. Cells in culture expressing in vivo studies demonstrate RAGE interaction with amyloid. Whereas cellular perturbation consequent to Abeta-RAGE interaction causes sustained activation in microglia, we predict that, over time, similar activation in neurons predisposes to several cell dysfunction and death. In AD brain, RAGE is expressed at high levels in neurons and activated microglia proximal to Abeta deposits, and increased levels of RAGE are also seen in transgenic (Tg) mice over-expressing mutant human (h) APP. We hypothesize that increased RAGE in AD brain provides a pivotal cofactor promoting neuronal stress, as reflected by neuronal dysfunction at the earliest stages of AD. i.e., before high concentration of Abeta are achieved. Our project utilizes Tg mice with targeted with over-expression of RAGE in neurons (aim 1), microglia (aim 2) or both cell types (aim 3) to determine whether they display enhanced neuronal stress in a Abeta- rich environment, the latter provided by over-expression of mutant betaAPP on the PDGF B chain promoter (neuropathologic, electrophysiologic, biochemical and behavioral endpoints will be studied). Our pilot studies with Tg PD-RAGE/hAPP mice show increased expression of cell stress markers, Interleukin 6 and Macrophage Colony Stimulating Factor, and NF-kappaB activation, compared with singly- transgenic mice. In view of the close relationship between ischemic episodes and the clinical course of AD/amyloid angiopathy, the response of these mice to ischemic stress will also be evaluated. Project 1 will work closely with Projects 2-4 and will obtain technical assistance from Core B. Collaborative interactions include: exchange of reagents/techniques related to RAGE biology (Project 2), evaluation of cellular stress (Projects 3-4), and neuropathologic analysis (Core B).